Abstract
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondria biogenesis and cell stress playing a role in metabolic and degenerative diseases. In the brain PGC-1α expression has been localized mainly to GABAergic interneurons but its overall role is not fully understood. We observed here that the protein levels of γ-aminobutyric acid (GABA) type A receptor-α2 subunit (GABARα2) were increased in hippocampus and brain cortex in transgenic (Tg) mice overexpressing PGC-1α in neurons. Along with this, GABARα2 expression was enhanced in the hippocampus of the PGC-1α Tg mice, as shown by quantitative PCR. Double immunostaining revealed that GABARα2 co-localized with the synaptic protein gephyrin in higher amounts in the striatum radiatum layer of the hippocampal CA1 region in the Tg compared with Wt mice. Electrophysiology revealed that the frequency of spontaneous and miniature inhibitory postsynaptic currents (mIPSCs) was increased in the CA1 region in the Tg mice, indicative of an augmented GABAergic transmission. Behavioral tests revealed an increase for anxiety-like behavior in the PGC-1α Tg mice compared with controls. To study whether drugs acting on PPARγ can affect GABARα2, we employed pioglitazone that elevated GABARα2 expression in primary cultured neurons. Similar results were obtained using the specific PPARγ agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine hydrate (GW1929). These results demonstrate that PGC-1α regulates GABARα2 subunits and GABAergic neurotransmission in the hippocampus with behavioral consequences. This indicates further that drugs like pioglitazone, widely used in the treatment of type 2 diabetes, can influence GABARα2 expression via the PPARγ/PGC-1α system.
Highlights
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is an important regulator of mitochondrial biogenesis, metabolism, and cell stress (Puigserver and Spiegelman, 2003; St-Pierre et al, 2006; Scarpulla, 2011)
Using immunoblotting and qPCR we observed that the expression of γ-aminobutyric acid type A receptor-α2 subunit (GABARα2) subunit was enhanced in the hippocampus of Tg mice compared with Wt animals. These results demonstrate that stimulation of the peroxisome proliferator-activated receptor γ (PPARγ)/PGC-1α system is involved in the regulation of GABARα2 expression and GABAergic neurotransmission in hippocampus with effects on behavior
We observed an increase in the level of GABARα2 subunit prompting further investigations. qPCR analyses revealed that the expression of GABARα2 was increased in hippocampus of the PGC-1α Tg mice compared with Wt using Gapdh as control (Figure 1A)
Summary
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is an important regulator of mitochondrial biogenesis, metabolism, and cell stress (Puigserver and Spiegelman, 2003; St-Pierre et al, 2006; Scarpulla, 2011). PGC-1α interacts with nuclear receptors, such as the peroxisome proliferator-activated receptor γ (PPARγ), affecting the expression of metabolic and other genes (Handschin and Spiegelman, 2006). PPARγ is present in the nervous system, and stimulation of the receptor exerts neuroprotective effects by reducing inflammation and oxidative stress in the brain (Austin and St-Pierre, 2012; Chen et al, 2012; Zolezzi et al, 2013). The underlying mechanisms of how PPARγ signaling influences behavior and neuronal connectivity are not fully understood
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